• environment
• genetics
• human immune response variation
• natural selection
• quantitative trait loci

• Humans
• Selection, Genetic
• Animals
• Genetic Predisposition to Disease
• Immunity/genetics
• Genetic Variation
• Genetics, Population
• Phenotype
• Disease Susceptibility/immunology

• R01-GM134376 NIH HHS
• P30-DK042086 NIH HHS
• James H. Gilliam Fellowship for Advanced Study Howard Hughes Medical Institute
• R01 GM134376 NIGMS NIH HHS
• AI07647 NIH HHS
• P30 DK042086 NIDDK NIH HHS

• gut microbiome
• infectious colitis
• inflammatory bowel syndrome
• ulcerative colitis (uc)
• yersinia enterocolitica

• Male
• Animals
• Mice
• Dextran Sulfate/adverse effects
• Wine
• Anthocyanins/pharmacology
• Anthocyanins/therapeutic use
• Dysbiosis/microbiology
• Mice, Inbred C57BL
• Colitis/chemically induced
• Colitis/drug therapy
• Colitis/pathology
• Colon
• Vitis
• Disease Models, Animal

• infection
• mucosal immunology
• interleukins
• antimicrobial responses

• Animals
• Crohn Disease/microbiology
• Crohn Disease/pathology
• Dysbiosis/microbiology
• Escherichia coli/immunology
• Escherichia coli Infections/immunology
• Immunity, Mucosal/immunology
• Interferon-gamma/immunology
• Interleukin-18/genetics
• Interleukin-18/immunology
• Interleukins/immunology
• Intestinal Mucosa/cytology
• Intestinal Mucosa/immunology
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muramidase/metabolism
• Organoids
• Paneth Cells/immunology
• Promoter Regions, Genetic/genetics
• STAT3 Transcription Factor/metabolism
• Tight Junctions/immunology
• Interleukin-22

• Academia Sinica
• Ministry of Science and Technology (MOST),106-2320-B-001-009-MY3 and 106-2321-B-016-003.

• 16S rRNA profiling
• fecal microbiota transplantation
• microbiome
• ulcerative colitis

• Adult
• Child
• Child, Preschool
• Crohn Disease/diagnosis
• Crohn Disease/microbiology
• Crohn Disease/therapy
• Humans
• Middle Aged
• Yersinia
• Yersinia Infections

The more complex data are, the higher the number of possibilities to extract partial information from those data. These possibilities arise by adopting different analytic approaches. The heterogeneity among these approaches and in particular the heterogeneity in results they produce are challenging for follow-up studies, including replication, validation and translational studies. Furthermore, they complicate the interpretation of findings with wide-spread relevance. Here, we take the example of statistical epistasis networks derived from genome-wide association studies with single nucleotide polymorphisms as nodes. Even though we are only dealing with a single data type, the epistasis detection problem suffers from many pitfalls, such as the wide variety of analytic tools to detect them, each highlighting different aspects of epistasis and exhibiting different properties in maintaining false positive control. To reconcile different network views to the same problem, we considered 3 network aggregation methods and discussed their performance in the context of epistasis network aggregation. We furthermore applied a latent class method as best performer to real-life data on inflammatory bowel disease (IBD) and highlighted its benefits to increase our understanding about IBD underlying genetic architectures.

• general surgery
• infection (gastroenterology)
• inflammatory bowel disease

Yersinia are common contaminants of food products, but their prevalence in the human gut is poorly documented. Yersinia have been implicated in Crohn's Disease (CD, an inflammatory bowel disease) however their role in CD is controversial. We performed highly sensitive PCR assays of specific sequences for the gyrB gene of Y. aldovae, Y. bercovieri, Y. enterocolitica, Y. intermedia, Y. mollaretii and the inv gene of Y. pseudotuberculosis. We analyzed a total of 470 ileal samples taken from 338 participants (262 CD patients and 76 controls) belonging to three independent cohorts. All patients and controls were phenotyped and genotyped for the main CD susceptibility variants: NOD2, ATG16L1, and IRGM. Yersinia were found in 7.7% of ileal samples (respectively 7.9 and 7.6% in controls and CD patients) corresponding to 10% of participants (respectively 11.8 and 9.5% in controls and CD patients). Y. enterocolitica, Y. pseudotuberculosis and Y. intermedia were the most frequently identified species. The bacteria were more frequent in resected specimens, lymph nodes and Peyer's patches. Yersinia were no more likely to be detected in CD tissues than tissues from inflammatory and non-inflammatory controls. CD patients treated with immunosuppressants were less likely to be Yersinia carriers. In conclusion, this work shows that Yersinia species are frequently found at low levels in the human ileum in health and disease. The role of Yersinia species in this ecosystem should now be explored.

• Crohn's disease
• gut microbiota
• ileal mucosa
• innate immunity
• molecular test
• mucosal immune system
• yersinia

• Animals
• Colicins/metabolism
• DNA, Recombinant/genetics
• Escherichia coli/genetics
• Escherichia coli/metabolism
• Escherichia coli/physiology
• Intestines/microbiology
• Mice
• Yersinia enterocolitica/physiology

• National Program of Sustainability: LO1218

• Animals
• Cells, Cultured
• Chronic Disease
• Colitis/immunology
• Genetic Predisposition to Disease
• Giardia/physiology
• Giardiasis/immunology
• Humans
• Interleukin-10/genetics
• Interleukin-10/metabolism
• Interleukin-12/metabolism
• Intestinal Mucosa/immunology
• Intestinal Mucosa/parasitology
• Intestine, Small/parasitology
• Intestine, Small/physiology
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Differentiation Factor 88/genetics
• Myeloid Differentiation Factor 88/metabolism
• Th1 Cells/immunology
• Toll-Like Receptors/metabolism

• KL2 TR000072 NCATS NIH HHS
• U01 AI075527 NIAID NIH HHS
• UL1 TR001439 NCATS NIH HHS
• R21 AI112594 NIAID NIH HHS
• U01 AI125860 NIAID NIH HHS

Ulcerative colitis (UC) is an inflammatory disease that mainly affects the colon and rectum. It is believed that genetic factors, host immune system disorders, intestinal microbiota dysbiosis, and environmental factors contribute to the pathogenesis of UC. However, studies on the role of intestinal microbiota in the pathogenesis of UC have been inconclusive. Studies have shown that probiotics improve intestinal mucosa barrier function and immune system function and promote secretion of anti-inflammatory factors, thereby inhibiting the growth of harmful bacteria in the intestine. Fecal microbiota transplantation (FMT) can reduce bowel permeability and thus the severity of disease by increasing the production of short-chain fatty acids, especially butyrate, which help maintain the integrity of the epithelial barrier. FMT can also restore immune dysbiosis by inhibiting Th1 differentiation, activity of T cells, leukocyte adhesion, and production of inflammatory factors. Probiotics and FMT are being increasingly used to treat UC, but their use is controversial because of uncertain efficacy. Here, we briefly review the role of intestinal microbiota in the pathogenesis and treatment of UC.

• Fecal microbiota transplantation
• Intestinal microbiota
• Ulcerative colitis
• Probiotics
• Mechanism
• Clinical application

• Animals
• Bacteria/growth & development
• Bacteria/immunology
• Colitis, Ulcerative/diagnosis
• Colitis, Ulcerative/immunology
• Colitis, Ulcerative/microbiology
• Colitis, Ulcerative/therapy
• Colon/immunology
• Colon/microbiology
• Fecal Microbiota Transplantation/adverse effects
• Gastrointestinal Microbiome
• Host-Pathogen Interactions
• Humans
• Probiotics/adverse effects
• Probiotics/therapeutic use
• Treatment Outcome

• bacteria/pathogen-host interaction
• commensal gut microbiota
• gnotobiotic animals
• gut–brain axis
• in vivo model
• inflammatory bowel diseases
• isolator-raised germfree animals
• secondary abiotic mice

• Inflammatory bowel diseases
• microbiota
• virome

Inflammatory bowel disease (IBD) is a chronic, non-specific inflammatory disease which mainly comprises Crohn's disease (CD) and ulcerative colitis (UC). Their etiologies and pathogenesis are still unclear. The role of gut microbiota in IBD has been gradually recognized in recent years. Two specific microorganisms (Mycobacterium avium subspecies paratuberculosis and Escherichia coli) were more widely studied. The microbiota also provides new therapeutic methods. Fecal microbiota transplantation (FMT) may restore the balance of intestinal flora to supplement or optimize current therapies. This article reviews the role and application of intestinal microbiota and FMT in IBD.

• Intestinal microbiota
• Ulcerative colitis
• Crohn's disease
• Fecal microbiota transplantation

A trillion of microorganisms colonize the mammalian intestine. Most of them have coevolved with the host in a symbiotic relationship and some of them have developed strategies to promote their replication in the presence of competing microbiota. Recent evidence suggests that perturbation of the microbial community favors the emergence of opportunistic pathogens, in particular adherent-invasive Escherichia coli (AIEC) that can increase incidence and severity of gut inflammation in the context of Crohn's disease (CD). This review will report the importance of AIEC as triggers of intestinal inflammation, focusing on their impact on epithelial barrier function and stimulation of mucosal inflammation. Beyond manipulation of immune response, restoration of gut microbiota as a new treatment option for CD patients will be discussed.

The intestinal microbiota plays an important role in inflammatory bowel disease (IBD). The pathogenesis of IBD involves inappropriate ongoing activation of the mucosal immune system driven by abnormal intestinal microbiota in genetically predisposed individuals. However, there are still no definitive microbial pathogens linked to the onset of IBD. The composition and function of the intestinal microbiota and their metabolites are indeed disturbed in IBD patients. The special alterations of gut microbiota associated with IBD remain to be evaluated. The microbial interactions and host-microbe immune interactions are still not clarified. Limitations of present probiotic products in IBD are mainly due to modest clinical efficacy, few available strains and no standardized administration. Fecal microbiota transplantation (FMT) may restore intestinal microbial homeostasis, and preliminary data have shown the clinical efficacy of FMT on refractory IBD or IBD combined with Clostridium difficile infection. Additionally, synthetic microbiota transplantation with the defined composition of fecal microbiota is also a promising therapeutic approach for IBD. However, FMT-related barriers, including the mechanism of restoring gut microbiota, standardized donor screening, fecal material preparation and administration, and long-term safety should be resolved. The role of intestinal microbiota and FMT in IBD should be further investigated by metagenomic and metatranscriptomic analyses combined with germ-free/human flora-associated animals and chemostat gut models.

• Inflammatory bowel disease
• Intestinal microbiota
• Probiotics
• Fecal microbiota transplantation
• Synthetic microbiota transplantation

• Animals
• Biological Therapy/methods
• Feces/microbiology
• Host-Pathogen Interactions
• Humans
• Immunity, Mucosal
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/microbiology
• Inflammatory Bowel Diseases/therapy
• Intestines/immunology
• Intestines/microbiology
• Microbiota
• Probiotics/therapeutic use
• Treatment Outcome

• BACTERIAL TRANSLOCATION
• CROHN'S DISEASE
• MOLECULAR BIOLOGY
• RIBOSOMAL RNA
• SURGICAL RESECTION

Our understanding of the microbial involvement in inflammatory bowel disease (IBD) pathogenesis has increased exponentially over the past decade. The development of newer molecular tools for the global assessment of the gut microbiome and the identification of nucleotide-binding oligomerization domain-containing protein 2 in 2001 and other susceptibility genes for Crohn’s disease in particular has led to better understanding of the aetiopathogenesis of IBD. The microbial studies have elaborated the normal composition of the gut microbiome and its perturbations in the setting of IBD. This altered microbiome or “dysbiosis” is a key player in the protracted course of inflammation in IBD. Numerous genome-wide association studies have identified further genes involved in gastrointestinal innate immunity (including polymorphisms in genes involved in autophagy: ATG16L1 and IGRM), which have helped elucidate the relationship of the local innate immunity with the adjacent luminal bacteria. These developments have also spurred the search for specific pathogens which may have a role in the metamorphosis of the gut microbiome from a symbiotic entity to a putative pathogenic one. Here we review advances in our understanding of microbial involvement in IBD pathogenesis over the past 10 years and offer insight into how this will shape our therapeutic management of the disease in the coming years.

• Inflammatory bowel disease
• Crohn’s disease
• Ulcerative colitis
• Gut microbiota
• Innate immune response
• Probiotics
• Prebiotics
• Faecal transplant

• Animals
• Bacteria/drug effects
• Bacteria/growth & development
• Bacteria/immunology
• Bacteria/pathogenicity
• Colitis, Ulcerative/genetics
• Colitis, Ulcerative/immunology
• Colitis, Ulcerative/microbiology
• Colitis, Ulcerative/therapy
• Crohn Disease/genetics
• Crohn Disease/immunology
• Crohn Disease/microbiology
• Crohn Disease/therapy
• Dysbiosis
• Genetic Predisposition to Disease
• Humans
• Immunity, Innate/genetics
• Immunity, Mucosal/genetics
• Intestines/immunology
• Intestines/microbiology
• Microbiota
• Phenotype
• Polymorphism, Single Nucleotide
• Risk Factors

In Lyme disease concurrent infections frequently occur. The clinical and pathological impact of co-infections was first recognized in the 1990th, i.e. approximately ten years after the discovery of Lyme disease. Their pathological synergism can exacerbate Lyme disease or induce similar disease manifestations. Co-infecting agents can be transmitted together with Borrelia burgdorferi by tick bite resulting in multiple infections but a fraction of co-infections occur independently of tick bite. Clinically relevant co-infections are caused by Bartonella species, Yersinia enterocolitica, Chlamydophila pneumoniae, Chlamydia trachomatis, and Mycoplasma pneumoniae. In contrast to the USA, human granulocytic anaplasmosis (HGA) and babesiosis are not of major importance in Europe. Infections caused by these pathogens in patients not infected by Borrelia burgdorferi can result in clinical symptoms similar to those occurring in Lyme disease. This applies particularly to infections caused by Bartonella henselae, Yersinia enterocolitica, and Mycoplasma pneumoniae. Chlamydia trachomatis primarily causes polyarthritis. Chlamydophila pneumoniae not only causes arthritis but also affects the nervous system and the heart, which renders the differential diagnosis difficult. The diagnosis is even more complex when co-infections occur in association with Lyme disease. Treatment recommendations are based on individual expert opinions. In antibiotic therapy, the use of third generation cephalosporins should only be considered in cases of Lyme disease. The same applies to carbapenems, which however are used occasionally in infections caused by Yersinia enterocolitica. For the remaining infections predominantly tetracyclines and macrolides are used. Quinolones are for alternative treatment, particularly gemifloxacin. For Bartonella henselae, Chlamydia trachomatis, and Chlamydophila pneumoniae the combination with rifampicin is recommended. Erythromycin is the drug of choice for Campylobacter jejuni.

• Bartonellosis
• Borellia burgdorferi
• Chlamydia trachomatis
• Chlamydophila pneumoniae
• Lyme disease
• Mycoplasma pneumoniae
• Yersinia enterocolitica.
• co-infection
• treatment

TLR1/TLR2 complexes are required for induction of IL-6 and IL-23 to generate protective T_H17-mediated immunity and IgA production after oral but not systemic Yersinia enterocolitica infection.

The balance between regulatory and inflammatory immune responses is critical to maintain intestinal homeostasis. Furthermore, the nature of the inflammatory response needs to be tailored to the tissue to provide proper protective immunity while preserving host integrity. TLR2 (Toll-like receptor 2) is a unique TLR in that it has been shown to promote regulatory and inflammatory T cell responses. Using Yersinia enterocolitica, we show that oral infection promotes T_H17 immunity, whereas systemic infection promotes T_H1 immunity. Furthermore, induction of T_H17 immunity during oral infection is dependent on TLR1 and results from the combinatorial effect of TLR2/TLR1-induced IL-6 and IL-23 and the presence of TGF-β in the intestinal environment. Interestingly, TLR2/TLR1 was not involved in T_H1 immune responses during systemic infection, whereas the TLR2/TLR6 receptor complex induced IL-10⁺ regulatory T cell responses during both systemic and oral infections. Our results reveal that the route of infection is central in determining which pathways provide protective immunity. Furthermore, they also demonstrate that TLR2 has dual immune functions in the gut and identify TLR1 as a critical innate receptor for protective intestinal T_H17 immunity.

• Bacteria
• Crohn
• Escherichia coli
• Inflammatory bowel disease
• Ulcerative colitis

Environmental risk factors playing a causative role in Crohn's Disease (CD) remain largely unknown. Recently, it has been suggested that refrigerated food could be involved in disease development. We thus conducted a pilot case control study to explore the association of CD with the exposure to domestic refrigeration in childhood.

Using a standard questionnaire we interviewed 199 CD cases and 207 age-matched patients with irritable bowel syndrome (IBS) as controls. Cases and controls were followed by the same gastroenterologists of tertiary referral clinics in Tehran, Iran. The questionnaire focused on the date of the first acquisition of home refrigerator and freezer. Data were analysed by a multivariate logistic model. The current age was in average 34 years in CD cases and the percentage of females in the case and control groups were respectively 48.3% and 63.7%. Patients were exposed earlier than controls to the refrigerator (X2 = 9.9, df = 3, P = 0.04) and refrigerator exposure at birth was found to be a risk factor for CD (OR = 2.08 (95% CI: 1.01–4.29), P = 0.05). Comparable results were obtained looking for the exposure to freezer at home. Finally, among the other recorded items reflecting the hygiene and comfort at home, we also found personal television, car and washing machine associated with CD.

This study supports the opinion that CD is associated with exposure to domestic refrigeration, among other household factors, during childhood.

For more than 2,000 years, it was thought that malignant spirits caused diseases. By the end of nineteenth century, these beliefs were displaced by more modern concepts of disease, namely, the formulation of the “germ theory,” which asserted that bacteria or other microorganisms caused disease. With the emergence of chronic degenerative and of autoimmune diseases in the last century, the causative role of microorganisms has been intensely debated; however, no clear explanatory models have been achieved. In this review, we examine the current available literature regarding the relationships between infections and 16 autoimmune diseases. We critically analyzed clinical, serological, and molecular associations, and reviewed experimental models of induction of and, alternatively, protection from autoimmune diseases by infection. After reviewing several studies and reports, a clinical and experimental pattern emerges: Chronic and multiple infections with viruses, such as Epstein–Barr virus and cytomegalovirus, and bacteria, such as H. pylori, may, in susceptible individuals, play a role in the evolvement of autoimmune diseases. As the vast majority of infections pertain to our resident microbiota and endogenous retroviruses and healthy carriage of infections is the rule, we propose to focus on understanding the mechanisms of this healthy carrier state and what changes its configurations to infectious syndromes, to the restoration of health, or to the sustaining of illness into a chronic state and/or autoimmune disease. It seems that in the development of this healthy carriage state, the infection or colonization in early stages of ontogenesis with key microorganisms, also called ‘old friends’ (lactobacilli, bifidobacteria among others), are important for the healthy living and for the protection from infectious and autoimmune syndromes.